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It gets people hooked on cigarettes, but researchers hope that nicotine and related compounds will have therapeutic uses.

Nicotine is rightly reviled because of its association with smoking and addiction. But new research has uncovered that the rogue substance has a wide range of effects on the brain, which may include some healing properties. Scientists are testing nicotine and related compounds as treatments for Alzheimer?s disease, Parkinson?s disease, attention deficit hyperactivity disorder (ADHD), and other conditions.

Self-medicating with cigarettes

The interest in nicotine?s therapeutic potential started in the 1980s. Several population based studies found that smokers had lower rates of Parkinson?s disease than nonsmokers. Epidemiolo?gists also validated what many mental health practitioners have long noticed: The smoking rate among people with schizophrenia, depression, and anxiety disorders is far higher than average. It?s widely believed that people with certain mental health problems are self-medicating with cigarettes because the nicotine helps their minds function better.

A most rewarding experience

Tobacco ? particularly when smoked ? is highly addictive. The cigarette sends the nicotine straight to the lungs, where it?s absorbed by the blood, carried to the heart, and pumped up to the brain. One aspect of addiction is withdrawal, and the symptoms of nicotine withdrawal usually begin within hours and consist of craving, irritability, anxiety, restlessness, and increased appetite. The craving may last for months ? even years.

The psychological effects of nicotine at first seem contradic?tory: increasing alertness while providing a sense of relaxation and calm. One possible explanation is that the effect varies with the user?s initial state. For someone who?s agitated, nicotine has a calming effect. For someone who isn?t, it heightens alert?ness. This difference may also help explain why nicotine, unlike many other addictive drugs, doesn?t behave in a simple additive manner as the dose increases.

Nicotine is addictive because it triggers a reaction in the brain?s reward system, the structures responsible for giving us pleasurable sensations. More specifically, the drug intensifies the activity of the neurotransmitter dopamine in a part of the brain called the nucleus accumbens. Cocaine and amphetamines do much the same thing; nicotine is tame in comparison. But experts theorize that it may have an added effect because the drug ampli?fies the brain?s response to the behaviours associated with smoking. In other words, it?s not just nicotine, but the pleasur?able sensation it confers on behaviours associated with smoking that make nicotine so addictive.

Nicotine can be addictive without cigarette smoke. For example, people become addicted to the nicotine in chewing tobacco and thambaku that is tucked next to the gums. As a rule, though, most drugs of abuse are not as addictive if they are delivered more gradually. In South America, coca leaves are chewed or used to make tea as a mild stimulant. Whatever the harmful effects, they?re a far cry from snorting cocaine. Methylphenidate (Rita?lin) is chemically more or less the same drug as the injectable amphetamines made in illicit laboratories. But in pill form for treatment of ADHD the effects on the brain are so much milder that it changes the character of the drug, despite the chemical similarities.

Effects outside the brain

Nicotine does have some negative cardiovascular effects, raising blood pressure and causing arteries to constrict, but it?s debat?able how significant they are. Doctors were initially quite concerned about prescribing the nicotine patch and other so-called nicotine replacement therapies for smokers with heart disease. But several studies in the mid-1990s showed that the nicotine replacements didn?t increase the number of heart attacks and strokes in these high-risk patients, so those worries have ebbed. Still, those were short-term studies, so cardiovascular harm from long term use might be a problem.

Most experts say nicotine itself does not cause cancer. It?s addictive, which gets people hooked on cigarettes, but the pre?vailing view has been that it is other substances in tobacco smoke (polycyclic aromatic hydrocarbons, tobacco-specific nitro?samine) that cause DNA damage and therefore cancer.

Nicotine?s imitators

Nicotine binds to the nerve cell receptors known as nicotinic or nicotinic acetylcholine receptors. Depending on the receptor and other factors, that binding may speed up the signaling between nerve cells or slow it down. There are at least a dozen nicotinic receptors; their functions are varied and overlap but often involve the processing of thoughts.

The molecules that snuggle into these receptors needn?t come from tobacco or nicotine. Dr. Paul A. Newhouse, director of the Uni?versity of Vermont?s Clinical Neuroscience Research Unit and for two decades a leading researcher in this field, says that one set of compounds now under investigation comes from a toxin in nemer?tine worms.

Drug companies are investing in nicotine-related compounds. Abbott Laboratories? ABT-418 has shown promise in treating ADHD. Taiho Pharmaceuticals has licensed a drug, code-named DMXB-A (also known as GTS-21), that is in early trials for the treatment of schizophrenia. Pfizer?s novel antismoking pill, Varenicline, is supposed to turn on nicotinic receptors just enough so smokers don?t go through withdrawal, but not enough to cause addiction.

Why so slow?

Researchers have been talking about nicotine-related drugs for decades, but none are on the market yet. Part of the problem is reputation. One researcher has suggested that nicotinic drugs be termed "cholinergic-channel modulators" to avoid the stigma. And it isn?t just image. Nicotine researchers have accepted money from tobacco companies. Targacept, a biopharmaceutical firm that focuses exclusively on this area of research, was part of R. J. Reynolds until 2000.

Even without these problems, designing nicotine-related drugs is tricky. Researchers must find compounds that are selective. "Nicotine is a pretty promiscuous drug," Dr. Newhouse explains. "It hits a lot of things at once. But for effective medications, we want to target specific receptors subtypes." Another obstacle is that nicotine-related compounds often have a fairly narrow therapeutic index: There isn?t much difference between a dose that?s helpful and one that?s toxic. That isn?t insurmountable, but it slows down clinical development.

Finally, the possibility that nicotine has angiogenic properties (see box "The Cancer Connection") may put a damper on the research. In a review article on nicotine and angiogenesis published last year in the Annals of Medicine, researchers John P. Cooke and Haim Bitterman said there was little reason to be worried about short-term use. In their opin?ion, nicotine gums and patches are safe and effective when "used as directed." But they called on scientists investigating the therapeutic potential of nicotine-like drugs to take the "potent angiogenic effects of nicotine" into account. Dr. Newhouse says the angiogenesis evidence comes largely from animal studies, so it doesn?t necessarily apply to humans. He also points to the good safety record of the patch and other nicotine replacements, while noting that there has been some legitimate concern about the development of insulin resistance.

Successful patchwork

Investigators are seeing if the nicotine patch might have other uses besides helping smokers quit. Last year, one trial found that the patch improved cognitive performance in patients with schizophrenia. A 2003 study investigated the effectiveness of nicotine patch therapy in nonsmoking patients diagnosed with depression. And a 2001 study reported promising results for treatment of Tourette?s disorder with a combination of the nico?tine patch and the antipsychotic drug haloperido.

In a 2004 Psychopharmacology article, Dr. Newhouse and Alexandra Potter, Ph.D., reported that the high smoking rate among adoles?cents and adults with ADHD could be explained by their discovery that nicotine improves aspects of their mental functioning. Potter is now recruiting people for two ADHD trials ? one in?volving nicotine and the other a drug called mecamylamine, which blocks certain nicotinic receptors.

An especially promising area of research involves cognitive impairments that are a precursor to Alzheimer?s disease. Last year, Duke University researchers published a small study on the effect of the nicotine patch in people with such impairments. They reported significant improvement in decision-making ability and attention (but not motor function or memory) in 11 subjects. Those results led to a larger study funded by the National Insti?tute on Aging.

Dr. Newhouse believes people are already using nicotine patches on their own for memory problems. "We get e-mails and letters inquiring about this almost every day," he says. "We still don?t have the data to recommend it. But we?re excited at the prospects and think the strategy looks pretty promising."

Express Delivery

Cigarettes are addictive because they are so efficient at deliv?ering nicotine to the brain.

1 The average smoker inhales 1-2 milligrams of nicotine per cigarette. The brain of a pack-a-day smoker gets 200 "hits" of the drug daily.

2 Tobacco smoke contains more than 50 known carcinogens ? but most experts say nicotine isn?t one of them.

3 Nicotine goes straight into the lungs and is rapidly absorbed by the oxygenated blood that the heart pumps throughout the body and brain.

4 The nicotine in cigarette smoke reaches the brain in just 10 seconds.

5 Nicotine stimulates the release of dopamine in the nucleus accumbens, the brain?s "reward centre." Behaviours surrounding smoking may also have an effect.